The sporadic nature of Alzheimer's disease argues for an environmental link that may drive AD pathogenesis; however, the triggering factors and the period of their action are unknown. Recent studies in rodents have shown that exposure to lead during brain development predetermined the expression and regulation of the amyloid precursor protein and its amyloidogenic beta-amyloid product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 ] as well as their transcriptional regulator were elevated in aged (...) monkeys exposed to Pb as infants. Furthermore, developmental exposure to Pb altered the levels, characteristics, and intracellular distribution of Abeta staining and amyloid plaques in the frontal association cortex. These latent effects were accompanied by a decrease in DNA methyltransferase activity and higher levels of oxidative damage to DNA, indicating that epigenetic imprinting in early life influenced the expression of AD-related genes and promoted DNA damage and pathogenesis. These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD. (shrink)

We assess J. Baird Callicott’s attempt in Earth’s Insights to reconcile his land ethic with the “environmental ethics” of indigenous peoples. We critique the rejection of ethical pluralism that informs this attempted rapprochement. We also assess Callicott’s strategy of grounding his land ethic in a postmodern scientific world view by contrasting it with the roles of “respect” and narrative in indigenous “ethics.”.

Alzheimer's disease is characterized by plaques of amyloid-beta peptide, cleaved from amyloid-beta protein precursor . Our hypothesis is that lifespan profiles of AD-associated mRNA and protein levels in monkeys would differ from mice and that differential lifespan expression profiles would be useful to understand human AD pathogenesis. We compared profiles of AbetaPP mRNA, AbetaPP protein, and Abeta levels in rodents and primates. We also tracked a transcriptional regulator of the AbetaPP gene, specificity protein 1 , and the beta amyloid precursor (...) cleaving enzyme . In mice, AbetaPP and SP1 mRNA and their protein products were elevated late in life; Abeta levels declined in old age. In monkeys, SP1, AbetaPP, and BACE1 mRNA declined in old age, while protein products and Abeta levels rose. Proteolytic processing in both species did not match production of Abeta. In primates, AbetaPP and SP1 mRNA levels coordinate, but an inverse relationship exists with corresponding protein products as well as Abeta levels. Comparison of human DNA and mRNA sequences to monkey and mouse counterparts revealed structural features that may explain differences in transcriptional and translational processing. These findings are important for selecting appropriate models for AD and other age-related diseases. (shrink)

This paper examines narrativism’s claim that the historical past cannot be known once and for all because it must be continuously re-described from the standpoint of the present. We argue that this claim is based on a non sequitur. We take narrativism’s claim that the past must be re-described continuously from the perspective of the present to be the result of the following train of thought: 1) “all knowledge is conceptually mediated”; 2) “the conceptual framework through which knowledge of reality (...) is mediated changes with every new generation of historians”; therefore (narrativism’s claim) “the historical past changes with every new generation of historians”. The idea of an unchanging past, for the narrativist, requires denying premise 1 (all knowledge is conceptually mediated”) and therefore rests on a problematic commitment to the chimerical notion of the past as it is in-itself, wie es eigentlich gewesen. We argue that the narrativist’s conclusion does not follow unless one adds a further premise, namely 3) “it is not possible to view reality through the categorial framework of historical agents”. If one asserts the possibility of grasping reality through the categorial framework of others, be they contemporary or past agents (as much philosophy of history written in an idealist key does), then one no longer has to accept the narrativist’s inference that since the past cannot be known in-itself or independently of conceptual mediation, then it cannot be known as it always was for the historical agents. Narrativism’s inference that the past cannot be known as it always was does not follow from premises 1 and 2 unless one smuggles in another problematic premise, premise 3. In this paper we defend the claim that the past can be known as it always was (not as it is in-itself) by invoking a different conception of the role of conceptual mediation in historical knowledge, one which assumes the possibility of viewing reality through the categorial framework of others. This notion of the role of conceptual mediation in historical knowledge is prevalent in the idealist tradition but, in the interest of brevity, we will defend this notion of mediacy by specific reference to the idealist philosophy of R.G. Collingwood. (shrink)

The Church of England By Law Established, in incidental payment for secular privilege, has submitted to the bonds of established clichá, in particular to the reproach that its rulers seem more concerned with the external or practical working of Anglican faith and ritual than with their intellectual definition and justification. This intellectual looseness remained unimportant in practice as long as a forceful anti–Roman spirit blew all waves of opinion in one practical direction. In time, however, that wind gradually lost force (...) and positive cross–currents of Anglican belief came to the public surface. The legislators of the sixteenth century had formulated the positive rules of the Thirty–Nine Articles and the Prayer Book in tolerantly broad language. They left no decisive teaching authority to explain their texts and to meet the challenge of shifting ritual and speculative doubt. Time has subjected both instruments to an everwidening range of individual interpretation especially since the early nineteenth century, when the Anglican monopoly of political, social and educational institutions was disputed by fresh tides of Protestant dissenters, renascent Catholics and nascent agnostics. To–day, as Mr. Cockshut wryly comments: “to throw doubt on the Anglican formularies is itself part of the Anglican tradition”. (shrink)

The meticulous printing at a moderate price of this remarkable work is a credit to the publisher. During the past thirty years M. Gilson has been the greatest single influence upon lay readers in reviving serious interest in the clerical speculation, which for twelve hundred years conscientiously spanned the gap between the collapse of Greek science and Roman law and the late sweep of modern sciences and their secular philosophies. Preoccupation with short-term apologetics after the Reformation increased clerical aloofness from (...) professional science and philosophy and probably increased the non-scholastic’s assumption that the Christian Era was merely a dark or middle age between ancient and modern intellectual life. In fact, early and medieval thinkers gradually confronted their Christian faith and pagan science and against the basso ostinato of secular warfare developed the varied themes of scientific theology and human philosophy, which crystallized into the mature Scholasticism of the thirteenth century. Hence the seventeenth century founders of modern philosophy, as M. Gilson first found à propos of Descartes, started to philosophize from a metaphysical inheritance much richer than the original Greek patrimony, especially in the light it cast upon the reality of God, the origin of the universe in which man lives, the nature and destiny of man himself. To overlook this linking inheritance, is to make modern philosophy less intelligible; while to personally judge its value, we must return to its historical sources. This is the task to which M. Gilson has devoted his pioneering judgment; this work is probably the final synthesis of his scholarship. (shrink)